Abstract
Aberrant activation of Wnt/β-catenin signaling pathway is essential for the development of AML; however, the mechanistic basis for this dysregulation is unclear. PRL-3 is an oncogenic phosphatase implicated in the development of LSCs. Here, we identified Leo1 as a direct and specific substrate of PRL-3. Serine-dephosphorylated form of Leo1 binds directly to β-catenin, promoting the nuclear accumulation of β-catenin and transactivation of TCF/LEF downstream target genes such as cyclin D1 and c-myc. Importantly, overexpression of PRL-3 in AML cells displayed enhanced sensitivity towards β-catenin inhibition in vitro and in vivo, suggesting that these cells are addicted to β-catenin signaling. Altogether, our study revealed a novel regulatory role of PRL-3 in the sustenance of aberrant β-catenin signaling in AML. PRL-3 may serve as a biomarker to select for the subset of AML patients who are likely to benefit from treatment with β-catenin inhibitors. Our study presents a new avenue of cancer inhibition driven by PRL-3 overexpression or β-catenin hyperactivation.
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Acknowledgements
This work was supported by the Singapore National Research Foundation and the Ministry of Education under the Research Center of Excellence Program to WJ Chng and NMRC Clinician-Scientist IRG Grant CNIG11nov38 to Zhou J. WJ Chng is supported by NMRC Singapore Translational Research (STaR) Investigatorship. This research is partly supported by the National Research Foundation Singapore and the Singapore Ministry of Education under the Research Centers of Excellence initiative as well as the RNA Biology Center at the Cancer Science Institute of Singapore, NUS, as part of funding under the Singapore Ministry of Education’s Tier 3 grants, grant number MOE2014-T3-1-006. No potential conflicts of interest were disclosed. We would also like to thank Prof Phil Koeffler, Prof Dan Tenen, Prof Toshio Suda, and Dr Motomi Osato for helpful discussions and critical reading of the manuscript.
Author contributions
PSY Chong, J Zhou, WJ Chng conceptualized and designed the experiments. PSY Chong, Chooi JY, EZL Chan, SHM Toh conducted the experiments and mouse work. S. Wee, J Gunaratne performed the MS analysis and bioinformatics. Zeng Q. provided material support. PSY Chong, J Zhou, WJ Chng wrote and reviewed the paper. None of the material has been published or is under consideration for publication elsewhere.
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Chong, P.S.Y., Zhou, J., Chooi, JY. et al. Non-canonical activation of β-catenin by PRL-3 phosphatase in acute myeloid leukemia. Oncogene 38, 1508–1519 (2019). https://doi.org/10.1038/s41388-018-0526-3
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DOI: https://doi.org/10.1038/s41388-018-0526-3
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